Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies

European Journal of Medicinal Chemistry

Volumn 109, Issue , 2016, Pages 216-237

  Migliore, Marco ^a   Habrant, Damien ^a,c   Sasso, Oscar ^a   Albani, Clara ^a,d   Bertozzi, Sine Mandrup ^a   Armirotti, Andrea ^a   Piomelli, Daniele ^a,b   Scarpelli, Rita ^a  

^a ISTITUTO ITALIANO DI TECNOLOGIA   (Italy)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c In Cell Art   (France)

^d Covagen AG ^*  (Switzerland)

Author keywords

COX; FAAH; Hybrid scaffold; Inflammation; Multitarget inhibitors; Structure activity relationship

Indexed keywords

2 [3 CHLORO 4 [3 (HEXYLCARBAMOYLOXY)PHENYL]PHENYL]PROPANOIC ACID; 2 [3 FLUORO 4 [3 (HEXYLCARBAMOYLOXY)PHENYL]PHENYL]ACETIC ACID; 2 [3 FLUORO 4 [3 (HEXYLCARBAMOYLOXY)PHENYL]PHENYL]PROPANOIC ACID; 2 [4 [3 (HEXYLCARBAMOYLOXY)PHENYL] 3 (TRIFLUOROMETHYL)PHENYL]PROPANOIC ACID; 2 [4 [3 (HEXYLCARBAMOYLOXY)PHENYL] 3 METHYLPHENYL]PROPANOIC ACID; 2 [4 [3 (HEXYLCARBAMOYLOXY)PHENYL]PHENYL]PROPANOIC ACID; ANALGESIC AGENT; ANTIINFLAMMATORY AGENT; ENZYME INHIBITOR; FATTY ACID AMIDASE; PROSTAGLANDIN SYNTHASE; UNCLASSIFIED DRUG; AMIDASE; CYCLOOXYGENASE 1; CYCLOOXYGENASE 2; FATTY-ACID AMIDE HYDROLASE; NONSTEROID ANTIINFLAMMATORY AGENT; PROSTAGLANDIN SYNTHASE INHIBITOR;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DRUG DESIGN; DRUG EFFECT; DRUG POTENCY; DRUG STRUCTURE; DRUG TARGETING; ENANTIOMER; ENZYME INHIBITION; IN VIVO STUDY; MALE; MOUSE; NONHUMAN; RAT; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMISTRY; HUMAN; METABOLISM; STEREOISOMERISM;

AMIDOHYDROLASES; ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; CYCLOOXYGENASE 1; CYCLOOXYGENASE 2; CYCLOOXYGENASE INHIBITORS; DRUG DESIGN; HUMANS; MICE; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84954051453     PISSN: 02235234     EISSN: 17683254     Source Type: Journal    
DOI: 10.1016/j.ejmech.2015.12.036     Document Type: Article

References (69)

1. J. Steinmeyer Pharmacological basis for the therapy of pain and inflammation with nonsteroidal anti-inflammatory drugs Arthritis Res. 2 2000 379 385
2. J.F. Fries NSAID gastropathy: the second most deadly rheumatic disease? Epidemiology and risk appraisal J. Rheumatol. Suppl. 28 1991 6 10
3. R. Tamblyn, L. Berkson, W.D. Dauphinee, D. Gayton, R. Grad, A. Huang, L. Isaac, P. McLeod, and L. Snell Unnecessary prescribing of NSAIDs and the management of NSAID-related gastropathy in medical practice Ann. Intern Med. 127 1997 429 438
4. B.K. Reuter, N.M. Davies, and J.L. Wallace Nonsteroidal anti-inflammatory drug enteropathy in rats: role of permeability, bacteria, and enterohepatic circulation Gastroenterology 112 1997 109 117
5. N.M. Davies, and J.L. Wallace Nonsteroidal anti-inflammatory drug-induced gastrointestinal toxicity: new insights into an old problem J. Gastroenterol. 32 1997 127 133
6. A.L. Blobaum, and L.J. Marnett Structural and functional basis of cyclooxygenase inhibition J. Med. Chem. 50 2007 1425 1441
7. J.L. Wallace NSAID gastroenteropathy: past, present and future Can. J. Gastroenterol. 10 1996 451 459
8. J.L. Wallace Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn′t the stomach digest itself? Physiol. Rev. 88 2008 1547 1565
9. J.L. Wallace, and L. Vong NSAID-induced gastrointestinal damage and the design of GI-sparing NSAIDs Curr. Opin. Investig. Drugs 9 2008 1151 1156
10. E. Ricciotti, and G.A. FitzGerald Prostaglandins and inflammation Arterioscler. Thromb. Vasc. Biol. 31 2011 986 1000
11. J.A. Mitchell, and T.D. Warner COX isoforms in the cardiovascular system: understanding the activities of non-steroidal anti-inflammatory drugs Nat. Rev. Drug Discov. 5 2006 75 86
12. J. Zhang, E.L. Ding, and Y. Song Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials JAMA 296 2006 1619 1632
13. C.A. Rouzer, and L.J. Marnett Endocannabinoid oxygenation by cyclooxygenases, lipoxygenases, and cytochromes P450: cross-talk between the eicosanoid and endocannabinoid signaling pathways Chem. Rev. 111 2011 5899 5921
14. F. Piscitelli, and V. Di Marzo "Redundancy" of endocannabinoid inactivation: new challenges and opportunities for pain control ACS Chem. Neurosci. 3 2012 356 363
15. S. Maione, B. Costa, and V. Di Marzo Endocannabinoids: a unique opportunity to develop multitarget analgesics Pain 154 Suppl. 1 2013 S87 S93
16. J.L. Wallace, L.J. Ignarro, and S. Fiorucci Potential cardioprotective actions of no-releasing aspirin Nat. Rev. Drug Discov. 1 2002 375 382
17. L. Lazzarato, M. Donnola, B. Rolando, E. Marini, C. Cena, G. Coruzzi, E. Guaita, G. Morini, R. Fruttero, A. Gasco, S. Biondi, and E. Ongini Searching for new NO-donor aspirin-like molecules: a new class of nitrooxy-acyl derivatives of salicylic acid J. Med. Chem. 51 2008 1894 1903
18. R.R. Ranatunge, M. Augustyniak, U.K. Bandarage, R.A. Earl, J.L. Ellis, D.S. Garvey, D.R. Janero, L.G. Letts, A.M. Martino, M.G. Murty, S.K. Richardson, J.D. Schroeder, M.J. Shumway, S.W. Tam, A.M. Trocha, and D.V. Young Synthesis and selective cyclooxygenase-2 inhibitory activity of a series of novel, nitric oxide donor-containing pyrazoles J. Med. Chem. 47 2004 2180 2193
19. K. Chegaev, L. Lazzarato, P. Tosco, C. Cena, E. Marini, B. Rolando, P.A. Carrupt, R. Fruttero, and A. Gasco NO-donor COX-2 inhibitors. New nitrooxy-substituted 1,5-diarylimidazoles endowed with COX-2 inhibitory and vasodilator properties J. Med. Chem. 50 2007 1449 1457
20. J.L. Wallace Hydrogen sulfide-releasing anti-inflammatory drugs Trends Pharmacol. Sci. 28 2007 501 505
21. J.L. Wallace, G. Caliendo, V. Santagada, G. Cirino, and S. Fiorucci Gastrointestinal safety and anti-inflammatory effects of a hydrogen sulfide-releasing diclofenac derivative in the rat Gastroenterology 132 2007 261 271
22. J.L. Wallace, G. Caliendo, V. Santagada, and G. Cirino Markedly reduced toxicity of a hydrogen sulphide-releasing derivative of naproxen (ATB-346) Br. J. Pharmacol. 159 2010 1236 1246
23. C. Charlier, and C. Michaux Dual inhibition of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) as a new strategy to provide safer non-steroidal anti-inflammatory drugs Eur. J. Med. Chem. 38 2003 645 659
24. P.N. Rao, Q.H. Chen, and E.E. Knaus Synthesis and structure-activity relationship studies of 1,3-diarylprop-2-yn-1-ones: dual inhibitors of cyclooxygenases and lipoxygenases J. Med. Chem. 49 2006 1668 1683
25. S.H. Hwang, K.M. Wagner, C. Morisseau, J.Y. Liu, H. Dong, A.T. Wecksler, and B.D. Hammock Synthesis and structure-activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase J. Med. Chem. 54 2011 3037 3050
26. M. Seierstad, and J.G. Breitenbucher Discovery and development of fatty acid amide hydrolase (FAAH) inhibitors J. Med. Chem. 51 2008 7327 7343
27. M.T. Cocco, C. Congiu, V. Onnis, M. Morelli, and O. Cauli Synthesis of ibuprofen heterocyclic amides and investigation of their analgesic and toxicological properties Eur. J. Med. Chem. 38 2003 513 518
28. S. Holt, B. Paylor, L. Boldrup, K. Alajakku, S. Vandevoorde, A. Sundstrom, M.T. Cocco, V. Onnis, and C.J. Fowler Inhibition of fatty acid amide hydrolase, a key endocannabinoid metabolizing enzyme, by analogues of ibuprofen and indomethacin Eur. J. Pharmacol. 565 2007 26 36
29. K.C. Duggan, D.J. Hermanson, J. Musee, J.J. Prusakiewicz, J.L. Scheib, B.D. Carter, S. Banerjee, J.A. Oates, and L.J. Marnett (R)-Profens are substrate-selective inhibitors of endocannabinoid oxygenation by COX-2 Nat. Chem. Biol. 7 2011 803 809
30. A.D. Favia, D. Habrant, R. Scarpelli, M. Migliore, C. Albani, S.M. Bertozzi, M. Dionisi, G. Tarozzo, D. Piomelli, A. Cavalli, and M. De Vivo Identification and characterization of Carprofen as a multitarget fatty acid amide Hydrolase/Cyclooxygenase inhibitor J. Med. Chem. 55 2012 8807 8826
31. M.A. Windsor, D.J. Hermanson, P.J. Kingsley, S. Xu, B.C. Crews, W. Ho, C.M. Keenan, S. Banerjee, K.A. Sharkey, and L.J. Marnett Substrate-selective inhibition of cyclooxygenase-2: development and evaluation of achiral profen probes ACS Med. Chem. Lett. 3 2012 759 763
32. C.J. Fowler, E. Bjorklund, A.H. Lichtman, P.S. Naidu, C. Congiu, and V. Onnis Inhibitory properties of ibuprofen and its amide analogues towards the hydrolysis and cyclooxygenation of the endocannabinoid anandamide J. Enzyme Inhib. Med. Chem. 28 2013 172 182
33. M. Cipriano, E. Bjorklund, A.A. Wilson, C. Congiu, V. Onnis, and C.J. Fowler Inhibition of fatty acid amide hydrolase and cyclooxygenase by the N-(3-methylpyridin-2-yl)amide derivatives of flurbiprofen and naproxen Eur. J. Pharmacol. 720 2013 383 390
34. C.N. Serhan, N. Chiang, and T.E. Van Dyke Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators Nat. Rev. Immunol. 8 2008 349 361
35. C. Morisseau, and B.D. Hammock Impact of soluble epoxide hydrolase and epoxyeicosanoids on human health Annu. Rev. Pharmacol. Toxicol. 53 2013 37 58
36. F. Massa, G. Marsicano, H. Hermann, A. Cannich, K. Monory, B.F. Cravatt, G.L. Ferri, A. Sibaev, M. Storr, and B. Lutz The endogenous cannabinoid system protects against colonic inflammation J. Clin. Invest. 113 2004 1202 1209
37. M.T. Cencioni, V. Chiurchiu, G. Catanzaro, G. Borsellino, G. Bernardi, L. Battistini, and M. Maccarrone Anandamide suppresses proliferation and cytokine release from primary human T-lymphocytes mainly via CB2 receptors PLoS One 5 2010 e8688
38. V. Chiurchiu, M.T. Cencioni, E. Bisicchia, M. De Bardi, C. Gasperini, G. Borsellino, D. Centonze, L. Battistini, and M. Maccarrone Distinct modulation of human myeloid and plasmacytoid dendritic cells by anandamide in multiple sclerosis Ann. Neurol. 73 2013 626 636
39. J. Fu, S. Gaetani, F. Oveisi, J. Lo Verme, A. Serrano, F. Rodriguez De Fonseca, A. Rosengarth, H. Luecke, B. Di Giacomo, G. Tarzia, and D. Piomelli Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha Nature 425 2003 90 93
40. J. LoVerme, R. Russo, G. La Rana, J. Fu, J. Farthing, G. Mattace-Raso, R. Meli, A. Hohmann, A. Calignano, and D. Piomelli Rapid broad-spectrum analgesia through activation of peroxisome proliferator-activated receptor-alpha J. Pharmacol. Exp. Ther. 319 2006 1051 1061
41. M. Suardiaz, G. Estivill-Torrus, C. Goicoechea, A. Bilbao, and F. Rodriguez de Fonseca Analgesic properties of oleoylethanolamide (OEA) in visceral and inflammatory pain Pain 133 2007 99 110
42. D.E. Wilson Role of prostaglandins in gastroduodenal mucosal protection J. Clin. Gastroenterol. 13 Suppl. 1 1991 S65 S71
43. K. Wright, N. Rooney, M. Feeney, J. Tate, D. Robertson, M. Welham, and S. Ward Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing Gastroenterology 129 2005 437 453
44. P.S. Naidu, L. Booker, B.F. Cravatt, and A.H. Lichtman Synergy between enzyme inhibitors of fatty acid amide hydrolase and cyclooxygenase in visceral nociception J. Pharmacol. Exp. Ther. 329 2009 48 56
45. O. Sasso, R. Bertorelli, T. Bandiera, R. Scarpelli, G. Colombano, A. Armirotti, G. Moreno-Sanz, A. Reggiani, and D. Piomelli Peripheral FAAH inhibition causes profound antinociception and protects against indomethacin-induced gastric lesions Pharmacol. Res. 65 2012 553 563
46. T.W. Grim, S. Ghosh, K.L. Hsu, B.F. Cravatt, S.G. Kinsey, and A.H. Lichtman Combined inhibition of FAAH and COX produces enhanced anti-allodynic effects in mouse neuropathic and inflammatory pain models Pharmacol. Biochem. Behav. 124 2014 405 411
47. D. Richardson, R.G. Pearson, N. Kurian, M.L. Latif, M.J. Garle, D.A. Barrett, D.A. Kendall, B.E. Scammell, A.J. Reeve, and V. Chapman Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis Arthritis Res. Ther. 10 2008 R43
48. A. Di Sabatino, N. Battista, P. Biancheri, C. Rapino, L. Rovedatti, G. Astarita, A. Vanoli, E. Dainese, M. Guerci, D. Piomelli, S.L. Pender, T.T. MacDonald, M. Maccarrone, and G.R. Corazza The endogenous cannabinoid system in the gut of patients with inflammatory bowel disease Mucosal Immunol. 4 2011 574 583
49. J. Suarez, Y. Romero-Zerbo, L. Marquez, P. Rivera, M. Iglesias, F.J. Bermudez-Silva, M. Andreu, and F. Rodriguez de Fonseca Ulcerative colitis impairs the acylethanolamide-based anti-inflammatory system reversal by 5-aminosalicylic acid and glucocorticoids PLoS One 7 2012 e37729
50. Singer II, D.W. Kawka, S. Schloemann, T. Tessner, T. Riehl, and W.F. Stenson Cyclooxygenase 2 is induced in colonic epithelial cells in inflammatory bowel disease Gastroenterology 115 1998 297 306
51. O. Sasso, M. Migliore, D. Habrant, A. Armirotti, C. Albani, M. Summa, G. Moreno-Sanz, R. Scarpelli, and D. Piomelli Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti-inflammatory drug-dependent gastrointestinal damage FASEB J. 29 2015 2616 2627
52. S. Kathuria, S. Gaetani, D. Fegley, F. Valino, A. Duranti, A. Tontini, M. Mor, G. Tarzia, G. La Rana, A. Calignano, A. Giustino, M. Tattoli, M. Palmery, V. Cuomo, and D. Piomelli Modulation of anxiety through blockade of anandamide hydrolysis Nat. Med. 9 2003 76 81
53. G. Tarzia, A. Duranti, A. Tontini, G. Piersanti, M. Mor, S. Rivara, P.V. Plazzi, C. Park, S. Kathuria, and D. Piomelli Design, synthesis, and structure-activity relationships of alkylcarbamic acid aryl esters, a new class of fatty acid amide hydrolase inhibitors J. Med. Chem. 46 2003 2352 2360
54. M. Mor, S. Rivara, A. Lodola, P.V. Plazzi, G. Tarzia, A. Duranti, A. Tontini, G. Piersanti, S. Kathuria, and D. Piomelli Cyclohexylcarbamic acid 3′- or 4′-substituted biphenyl-3-yl esters as fatty acid amide hydrolase inhibitors: synthesis, quantitative structure-activity relationships, and molecular modeling studies J. Med. Chem. 47 2004 4998 5008
55. G. Tarzia, A. Duranti, G. Gatti, G. Piersanti, A. Tontini, S. Rivara, A. Lodola, P.V. Plazzi, M. Mor, S. Kathuria, and D. Piomelli Synthesis and structure-activity relationships of FAAH inhibitors: cyclohexylcarbamic acid biphenyl esters with chemical modulation at the proximal phenyl ring ChemMedChem 1 2006 130 139
56. M. Mor, A. Lodola, S. Rivara, F. Vacondio, A. Duranti, A. Tontini, S. Sanchini, G. Piersanti, J.R. Clapper, A.R. King, G. Tarzia, and D. Piomelli Synthesis and quantitative structure-activity relationship of fatty acid amide hydrolase inhibitors: modulation at the N-portion of biphenyl-3-yl alkylcarbamates J. Med. Chem. 51 2008 3487 3498
57. M. Mileni, S. Kamtekar, D.C. Wood, T.E. Benson, B.F. Cravatt, and R.C. Stevens Crystal structure of fatty acid amide hydrolase bound to the carbamate inhibitor URB597: discovery of a deacylating water molecule and insight into enzyme inactivation J. Mol. Biol. 400 2010 743 754
58. J.R. Clapper, G. Moreno-Sanz, R. Russo, A. Guijarro, F. Vacondio, A. Duranti, A. Tontini, S. Sanchini, N.R. Sciolino, J.M. Spradley, A.G. Hohmann, A. Calignano, M. Mor, G. Tarzia, and D. Piomelli Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism Nat. Neurosci. 13 2010 1265 1270
59. R.G. Kurumbail, A.M. Stevens, J.K. Gierse, J.J. McDonald, R.A. Stegeman, J.Y. Pak, D. Gildehaus, J.M. Miyashiro, T.D. Penning, K. Seibert, P.C. Isakson, and W.C. Stallings Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents Nature 384 1996 644 648
60. B.S. Selinsky, K. Gupta, C.T. Sharkey, and P.J. Loll Structural analysis of NSAID binding by prostaglandin H2 synthase: time-dependent and time-independent inhibitors elicit identical enzyme conformations Biochemistry 40 2001 5172 5180
61. C.I. Bayly, W.C. Black, S. Leger, N. Ouimet, M. Ouellet, and M.D. Percival Structure-based design of COX-2 selectivity into flurbiprofen Bioorg. Med. Chem. Lett. 9 1999 307 312
62. G. Lu, R. Franzén, X.J. Yu, and Y.J. Xu Synthesis of flurbiprofen via Suzuki reaction catalyzed by Palladium charcoal in water Chin. Chem. Lett. 17 2006 461 464
63. A. Del Zotto, F. Amoroso, W. Baratta, and P. Rigo Very fast Suzuki-Miyaura reaction catalyzed by Pd(OAc)2 under aerobic conditions at room temperature in EGME/H2O Eur. J. Org. Chem. 2009 2009 110 116
64. S. Narasimhan, and R. Balakumar Zirconium borohydride - a versatile reducing agent for the reduction of electrophilic and nucleophilic substrates Synth. Commun. 30 2000 4387 4395
65. W.C. Bartolini, Brian M., Chen Barbara, Chien Yueh-Tyng, Currie Mark G., Milne Todd G., Pearson, J.J.Z. James Philip; Talley, Craig, Cyclooxygenase 2 (COX-2) and Fatty Acid Amide Hydrolase (FAAH) Inhibitors for Therapeutic Use, WO2005002525.
66. M.G. Malkowski, S.L. Ginell, W.L. Smith, and R.M. Garavito The productive conformation of arachidonic acid bound to prostaglandin synthase Science 289 2000 1933 1937
67. J.R. Kiefer, J.L. Pawlitz, K.T. Moreland, R.A. Stegeman, W.F. Hood, J.K. Gierse, A.M. Stevens, D.C. Goodwin, S.W. Rowlinson, L.J. Marnett, W.C. Stallings, and R.G. Kurumbail Structural insights into the stereochemistry of the cyclooxygenase reaction Nature 405 2000 97 101
68. G. Wider, and L. Dreier Measuring protein concentrations by NMR spectroscopy J. Am. Chem. Soc. 128 2006 2571 2576
69. I.W. Burton, M.A. Quilliam, and J.A. Walter Quantitative 1H NMR with external standards: use in preparation of calibration solutions for algal toxins and other natural products Anal. Chem. 77 2005 3123 3131